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Our dynamic trajectories reveal an enhancement in binding affinity between mutated RBD and the common receptor protein angiotensin converting enzyme 2 (ACE2) through a net increase in the buried molecular surface area of the binary complex. This enhanced binding, mediated through Gln493, sets the same stage for all three sublineages due to the presence of L452R mutation. The other mutation component, E484Q or T478K, was found to impact the RBD-ACE2 binding and help the variant to evade several monoclonal antibodies (mAbs) in a distinct manner. Especially for L452R + T478K, synergies between mutations are mediated through a complex residual and water interaction network and further enhance its binding to ACE2. Taking together, this study demonstrates that new variants of SARS-CoV-2 accomplish both \u201cattack\u201d (infection) and \u201cdefense\u201d (antibody neutralization escape) with the same \u201cpolished sword\u201d (mutated Spike RBD).<\/jats:p>","DOI":"10.3390\/biom12121742","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T01:46:56Z","timestamp":1669254416000},"page":"1742","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["SARS-CoV-2 Delta Variant: Interplay between Individual Mutations and Their Allosteric Synergy"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3705-1835","authenticated-orcid":false,"given":"Kevin C.","family":"Chan","sequence":"first","affiliation":[{"name":"Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Shanghai Institute for Advanced Study, Zhejiang University, 799 Dangui Road, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Song","sequence":"additional","affiliation":[{"name":"Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0113-0010","authenticated-orcid":false,"given":"Zheng","family":"Xu","sequence":"additional","affiliation":[{"name":"BirenTech Research, Shanghai 201112, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Shang","sequence":"additional","affiliation":[{"name":"Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruhong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Shanghai Institute for Advanced Study, Zhejiang University, 799 Dangui Road, Shanghai 201203, China"},{"name":"Department of Chemistry, Columbia University, New York, NY 10027, USA"},{"name":"The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.cell.2022.01.019","article-title":"Structural and Functional Characterizations of Infectivity and Immune Evasion of SARS-CoV-2 Omicron","volume":"185","author":"Cui","year":"2022","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/j.cell.2022.01.001","article-title":"Receptor Binding and Complex Structures of Human ACE2 to Spike RBD from Omicron and Delta SARS-CoV-2","volume":"185","author":"Han","year":"2022","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41392-021-00863-2","article-title":"SARS-CoV-2 Omicron RBD Shows Weaker Binding Affinity than the Currently Dominant Delta Variant to Human ACE2","volume":"7","author":"Wu","year":"2022","journal-title":"Signal Transduct. 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